One of steroid hormones, androgen, and a receptor thereof, i.e., an androgen receptor (AR, hereinafter also referred to as AR), are known as being closely involved with proliferation and even canceration of prostate cells.
Therefore, an androgen ablation therapy inhibiting the activity of AR to suppress progression of prostate cancer has been performed as one of the treatment methods of prostate cancer. However, this treatment has a problem that the effect disappears as the treatment proceeds due to a change in characteristics of the prostate cancer cells, making the subsequent treatment difficult.
Since the prostate cancer cells expressing AR show the enhanced expression of androgen response genes, methods such as administering interfering RNA and antisense nucleic acids to the androgen response genes to destabilize the expression of these genes to treat prostate cancer, and administrating an expression vector containing a polynucleotide coding a cytotoxic gene product to cancer cells to treat prostate cancer has been disclosed (Patent Documents 1 to 4).
However the interfering RNA and the antisense nucleic acids are easily degraded and less stable in a living body. In addition, the method including the expression of the cytotoxic gene product in a living body is not considered safe. Therefore, these treatment methods are not considered as adequate methods for treatment of prostate cancer.
Thus, to acquire a stable and safe substance effective for treatment of prostate cancer, the present inventors focused on a PI polyamide sequence-specifically binding to DNA and having high in-vivo stability and high transferability to tissues and cells (Non-Patent Document 1). PI polyamide is a substance composed of aromatic amino acids N-methylpyrrole (hereinafter also referred to as Py) and N-methylimidazole (hereinafter also referred to as Im).
The present inventors developed a PI polyamide inhibiting expression of a fusion gene between an androgen response gene TMPRSS2 and an ERG gene belonging to the ETS family that is one of the largest families of transcriptional factors (Japanese Patent Application No. 2012-106382). This PI polyamide developed by the present inventors inhibits the expression of the fusion gene between the TMPRSS2 gene and the ERG gene and is also capable of inhibiting the expression of EZH2 gene occurring in association with the expression of this fusion gene. These data indicate that the PI polyamide is useful for prevention, treatment, etc. of prostate cancer.
Additionally, for the purpose of enabling comprehensive prevention, treatment, etc. of prostate cancer, the present inventors attempted in the present invention to develop a useful PI polyimide for an ACSL3 gene that is one of the androgen response genes. While the ACSL3 gene is an androgen response gene related to metabolism of long-chain fatty acid and is known as being highly expressed in prostate cancer, the present inventors have found that the gene enhances the proliferation and the migration ability of prostate cancer cells.
The present inventors found that a transcriptional regulatory region (AR response region) is located 63 kb upstream of the transcription start point of the ACSL3 gene and that two Oct1 gene binding sequences and a GATA gene binding sequence are located as transcription factors in the vicinity of a site at which AR binds to a gene (AR response element, hereinafter also referred to as ARE). The present inventors also found that one of this Oct1 gene binding sequence is a poor-prognosis factor of prostate cancer positively enhancing the transcription activity of AR (Non-Patent Document 2).
Therefore, in the present invention, the present inventors developed a PI polyamide specifically binding to this Oct1 gene binding sequence in an attempt to develop a PI polyamide inhibiting the expression of the ACSL3 gene and therefore useful for prevention, treatment, etc. of prostate cancer.